1. Field of the Invention
The present invention generally relates to the field of analyte detection and additionally relates to detecting analytes using magnetic resonance.
2. Related Art
Detection technology for specific analytes spans a wide range of laboratory instrumentation and techniques including liquid and gas chromatography (LC and GC, respectively), mass spectrometry (MS), nuclear magnetic resonance (NMR) spectroscopy, polymerase chain reaction (PCR), optical spectroscopy and fluoroscopy, Fourier transform infrared (FTIR) spectroscopy, and ion mobility instruments. Today's chemical analysis instruments however, are large and expensive, require a skilled operator, involve complex sample preparation, and require substantial amounts of time for analysis.
There is a critical need worldwide for improved detection of specific chemicals and microbes. For example, in the area of national security, a system is needed to detect biological agents, toxins, and chemical weapons to provide early alert in case of a terrorist attack. Such a detection capability could also be used to search for clandestine sites where such weapons are under development or in production, thus enabling action to prevent their use. A system is also needed to scan mail and packages to detect a terrorist attack.
Improved pathogen detection is also needed for medical science. Sensitive detection of DNA or proteins associated with avian flu, bovine spongiform encephalopathy (more commonly referred to as “mad-cow disease”), or severe acute respiratory syndrome (SARS) would enable intervention to avoid a pandemic. Broad clinical use of such a system would assist in identifying ordinary diseases or serious illnesses, greatly assisting physicians in diagnosis.
Detection of various chemicals is also needed for industrial applications to detect toxic industrial chemicals (TICs) and toxic industrial materials (TIMs). Such a system would enable leak detection, process control, detection of material degradation, control of concentration, and a host of other process applications in a wide range of industries.
Improved detection is also needed in agriculture and food production, as well as a means to detect contamination, spoiling, or poisoning of food. Food includes for example, items such as drinking water and fruit juices. There is also a need in forensic testing, including for example, searching for specific DNA sequences in a sample at the search site.
Magnetic resonance detection techniques are under development involving nanometer-scale paramagnetic particles (nanoparticles) which have previously been used as MRI contrast agents. The particles comprise a core of paramagnetic or superparamagnetic (both generally referred to herein as paramagnetic) material, coated by a shell of nonmagnetic material which are adorned with reactant molecules to promote binding to target cells such as pathogens, tumor cells, etc. Nanoparticles are injected into a patient prior to MRI analysis. They bind to the target cells, cause a local change in the MRI image properties, and enable detection or localization of the target cells.
The nanoparticles have also been used in vitro. Dissolved or suspended in a liquid medium, the nanoparticles bind to target cells or molecules in the medium. The nanoparticles and analytes may form aggregates incorporating dozens to thousands of nanoparticles. Such aggregates are detectable by light scattering, atomic-force microscopy, electron microscopy, and in some cases by NMR effects. See, for example, U.S. Pat. No. 5,254,460 to Josephson et al.
Target-specific reactants can be mounted onto the nanoparticles to provide analyte-specific selectivity. A disadvantage is the need to form aggregations comprising a plurality of nanoparticles and a plurality of target cells or molecules, because aggregation occurs only when each nanoparticle is bound to multiple analytes, and each analyte is bound to multiple nanoparticles. Aggregation can be inhibited by geometrical effects such as a variation in size among nanoparticles. Substantial time may be required for the aggregations to form.
Prior studies on agglomeration were conducted on benchtop relaxometers and high-field MR instruments. Manual sample preparation and insertion into the NMR tube can be tedious. Important events such as binding of the analyte to the nanoparticles may be missed. A compact and automated instrument is required to speed up measurements. Also, it is important to understand the phenomena describing the changes seen in the measurement from a basic physics and biochemistry standpoint.
Earlier studies did not model the change in T2 effects from a physics standpoint. Simple agglomeration effects were observed through optical means (microscopes) to establish the phenomena relating change in T2. In addition, early studies did not take advantage of stoichiometry control of the nanoparticles to adapt the measured parameters for various applications leading to specific NMR products.
Earlier studies used samples that were pure and not subject to interferences such as dust, acids, etc. Moreover, there was no requirement for fast measurements combined with no interference from clutter and near neighbor molecules, cost of overall system, low false alarms and high probability of detection. There was also no defined range of analyte concentrations to be detected.
Earlier studies did not consider use of improved paramagnetic materials such as compounds of iron, cobalt and nickel leading to stronger magnetization and improved sensitivity. Earlier studies did not consider use of magnetic fields to influence interactions between nanoparticles or between molecules attached to nanoparticles. Use of magnetic fields to control the formation or geometrical configuration of structures comprising nanoparticles and analytes has not been considered. Use of magnetic fields to concentrate reactants so as to accelerate selected interactions was not previously considered.